1. Field of the Invention
The present invention relates generally to a process for preparing histone deacetylase inhibitors, as well as intermediates thereof.
2. Related Art
Histone deacetylase (HDAC) inhibitors are promising compounds for the development of anti-cancer, as well as anti-malarial drugs. HDAC inhibitors include simple fatty acid compounds such as sodium butyrate, phenylbutyrate, and valproic acid, up to more complex cyclic tetrapeptide antibiotics such as apidicin, trapoxin B and depsipeptide. Most of the known HDAC inhibitors are hydroxamic acids or derivatives thereof such as trichostatin A (TSA) and suberoylanilide hydroxamic acid (SAHA). See Wang et al., “QSAR Studies of PC-3 Cell Line Inhibition Activity of TSA and SAHA-Like Hydroxamic Acids,” Bioorg, & Med. Chem. Lett., 14 (2004): pp. 707–11.
The most potent HDAC inhibitor discovered so far is TSA. TSA is a relatively rare natural product that was originally isolated from Streptomyces hygroscopicus. See Tsji et al., “New Antifungal Antibiotic, Trichostatin,” J. Antibiot., 29 (1976): pp. 1–6; Yoshida et al., “Trichostatin-A and Trapoxin—Novel Chemical Probes for the Role of Histone Acetylation in Chromatin Structure and Function,” BioEssay, 17 (1995): pp. 423–30. TSA has been previously synthesized as both racemic and enantiomerically pure forms. See Fleming et al., “The Total Synthesis of (+/−)-Trichostatin-A—Some Observations on the Acylation and Alkylation of Silyl Enol Ethers, Silyl Dienol Ethers and a Silyl Trienol Ether,” Tetrahedron, 39 (1983): pp. 841–46; K. Mori et al, “Synthetic Microbial Chemistry: Synthesis of Trichostatin-A, a Potent Differentiation Inducer of Friend Leukemic-Cells, and its Antipode,” Tetrahedron, 44 (1988): pp. 6013–20. However, these prior syntheses for TSA require a significant number synthesis steps (e.g., upwards of 20 synthesis steps), and are therefore relatively inefficient and impractical to economically produce TSA. Because these prior syntheses for producing TSA are inefficient, impractical and costly, others have searched for alternative HDAC inhibitors. Indeed, because of the difficulty in synthesizing TSA and the relatively high cost of TSA (e.g., ˜$100/mg.), TSA is used today mainly as a reference substance in the research for new HDAC inhibitors.
Accordingly, it would be desirable to provide a process for synthesizing TSA, including intermediates thereof, as well as other HDAC inhibitors, that: (1) requires fewer synthesis steps; (2) is more practical, (3) is more efficient; (4) is less expensive; and/or (5) has the processing flexibility to prepare a wide variety of HDAC inhibitors, and their respective intermediates, by using the same or similar processing steps.